Pregnancy and CYP3A5 Genotype Affect Day 7 Plasma Lumefantrine Concentrations

Drug Metab Dispos. 2019 Dec;47(12):1415-1424. doi: 10.1124/dmd.119.088062.


Pregnancy and pharmacogenetics variation alter drug disposition and treatment outcome. The objective of this study was to investigate the effect of pregnancy and pharmacogenetics variation on day 7 lumefantrine (LF) plasma concentration and therapeutic responses in malaria-infected women treated with artemether-lumefantrine (ALu) in Tanzania. A total of 277 (205 pregnant and 72 nonpregnant) women with uncomplicated Plasmodium falciparum malaria were enrolled. Patients were treated with ALu and followed up for 28 days. CYP3A4, CYP3A5, and ABCB1 genotyping were done. Day 7 plasma LF concentration and the polymerase chain reaction (PCR) - corrected adequate clinical and parasitological response (ACPR) at day 28 were determined. The mean day 7 plasma LF concentrations were significantly lower in pregnant women than nonpregnant women [geometric mean ratio = 1.40; 95% confidence interval (CI) of geometric mean ratio (1.119-1.1745), P < 0.003]. Pregnancy, low body weight, and CYP3A5*1/*1 genotype were significantly associated with low day 7 LF plasma concentration (P < 0.01). PCR-corrected ACPR was 93% (95% CI = 89.4-96.6) in pregnant women and 95.7% (95% CI = 90.7-100) in nonpregnant women. Patients with lower day 7 LF concentration had a high risk of treatment failure (mean 652 vs. 232 ng/ml, P < 0.001). In conclusion, pregnancy, low body weight, and CYP3A5*1 allele are significant predictors of low day 7 LF plasma exposure. In turn, lower day 7 LF concentration is associated with a higher risk of recrudescence. SIGNIFICANCE STATEMENT: This study reports a number of factors contributing to the lower day 7 lumefantrine (LF) concentration in women, which includes pregnancy, body weight, and CYP3A5*1/*1 genotype. It also shows that day 7 LF concentration is a main predictor of malaria treatment. These findings highlight the need to look into artemether-LF dosage adjustment in pregnant women so as to be able to maintain adequate drug concentration, which is required to reduce treatment failure rates in pregnant women.

Publication types

  • Observational Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antimalarials / administration & dosage*
  • Antimalarials / blood*
  • Antimalarials / therapeutic use
  • Artemether, Lumefantrine Drug Combination / administration & dosage*
  • Artemether, Lumefantrine Drug Combination / blood*
  • Artemether, Lumefantrine Drug Combination / therapeutic use
  • Cohort Studies
  • Cytochrome P-450 CYP3A / genetics*
  • Dose-Response Relationship, Drug
  • Female
  • Gene Frequency
  • Genotype
  • Humans
  • Malaria, Falciparum / blood
  • Malaria, Falciparum / drug therapy*
  • Malaria, Falciparum / genetics
  • Pregnancy
  • Pregnancy Complications, Parasitic / blood
  • Pregnancy Complications, Parasitic / drug therapy*
  • Pregnancy Complications, Parasitic / genetics
  • Pregnancy Trimester, Third
  • Prospective Studies
  • Time Factors


  • Antimalarials
  • Artemether, Lumefantrine Drug Combination
  • CYP3A5 protein, human
  • Cytochrome P-450 CYP3A